A key element in any structure based molecular design strategy is the capability of predicting the energetics of a putative interaction from structural considerations. This goal is greatly complicated by the fact that upon binding, the changes in the intrinsic interactions (protein-protein or in general protein-ligand) are accompanied by changes in the hydration of the interacting surfaces (protein-water interactions). Despite the impressive amount of information currently available regarding the interactions between proteins and a large number of ligand molecules (ions, sugars, lipids, peptides, etc.) in aqueous solution, our understanding of the molecular recognition processes between proteins and different ligands is still constrained by our limited knowledge of the role that the changes in the hydration state of the interacting species plays in the overall energetics. It seems evident that directly determining the energetics of hydration of proteins and ligands (peptides, nucleotides, etc.) would be clarifying not only in the understanding of such processes but in the development of empirical relationships between structural and thermodynamical changes. This objective can be achieved by determining the energetics associated with the hydration of anhydrous proteins (e.g., dissolution of anhydrous protein sample into buffered water). This thermodynamic data combined with structural information regarding the solvent accessibility of the protein surface would be used in the refinement of the empirical parameters that we are currently using in our structure-based thermodynamic calculations.